This proposal describes an efficient synthetic route to the anti-malarial drug, malagashanine, and related analogues. Malagashanine is an indole alkaloid isolated from the stem bark of Strychnos myrtoides and it has the ability to restore therapeutic concentrations of the drug, chloroquine, in drug-resistant strains of Plasmodium malaria. As such, malagashanine shows promise as a chloroquine adjuvant in drug combination therapy for the treatment of malaria. To date, the synthesis of this natural product has never been realized, and the biological community would greatly benefit from facile access to the compound through total synthesis to further study its biological mechanism of action. We propose the fused skeleton of these alkaloids can be assembled in a single step using an intramolecular [4+2]/[3+2] cycloaddition cascade strategy with direct introduction of structural and stereochemical diversity in a controlled manner. An alternative tethering approach of the initiating dienophile through the oxadiazole C16 substituent, rather than through the more common C3 amino substituent, will be used. The possibility of asymmetric induction by the C19 and C20 substituents will also be explored, as well as the synthesis of a variety of analogues that can be easily accessed using this strategy. These synthetic alkaloids can be tested against chloroquine-resistant malarial strains to reveal novel biological modes of action that could be used in the future design of chemotherapeutics. The Specific Aims of the proposed research are (1) to apply the tandem intramolecular [4+2]/[3+2] cycloaddition cascade methodology to the synthesis of malagashanine (2) to investigate the effect of asymmetric induction imparted by a chiral tether (3) to systematically explore analogues that cannot be easily accessed by any other strategy and (4) to provide sufficient quantities of malagashanine and related analogues for in vitro testing in drug-resistance malarial strains for structure-activity relationship (SAR) determination and mechanistic elucidation of its effect on chloroquine. PUBLIC HEALTH RELEVANCE: Malaria is the major parasitic infection in many tropical and subtropical regions with more than 500 million cases each year. New anti-malarial treatments are now a public health priority, following the emergence of resistance to the most used drugs. An efficient method to access the promising anti-malarial drugs of the malagashanine family through total synthesis described herein will directly aid in the fight against this detrimental disease by providing sufficient quantities for biological testing.